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Biomedical subjects

W D Alexander

Publications and source records attributed to W D Alexander.

At least 55 records · Page 3Linked to original sources
PubMed1984

Peroxidase activity in relation to iodide, 17 beta-oestradiol and thioureylene drug uptake in human polymorphoneutrophils.

In polymorphoneutrophils (PMNs) phagocytosis is accompanied by an increase in peroxidase activity. Accumulation of iodide, thioureylene antithyroid drugs and 17 beta-oestradiol also occurs during the process. There is no evidence of an active iodide transport system in the PMNs as pertechnetate is not concentrated and neither ouabain nor perchlorate abolishes iodide accumulation. The uptakes of 125I, [35S]PTU and [3H]-17 beta-oestradiol were compared in phagocytosing PMNs and the effects of various compounds examined. In addition, chemiluminescence generation from luminol by PMNs and by horseradish peroxidase was studied. This indicated that uptake of all three compounds could be associated with activation of the peroxidase system, and inhibition of this enzyme system caused a reduction in their accumulation.

Estradiol↗
PubMed1984

Effect of pretreatment with carbimazole on early outcome following radio-iodine (131I) therapy.

Of a group of 55 thyrotoxic patients given therapeutic radio-iodine (131I), 24 were made euthyroid with carbimazole before 131I: the remainder were given 131I alone. Carbimazole was discontinued 5 days before 131I was administered. By 3 months after 131I treatment there was a greater incidence of hypothyroidism in the group given 131I alone (42% vs 25%), but a lower incidence of persistent thyrotoxicosis (16% vs 46%), (P less than 0.05). One year after treatment a similar proportion of each group had persistent thyrotoxicosis (21% vs 23%), but there remained a lower incidence of hypothyroidism in the group pretreated with carbimazole (25% vs 45%). It is suggested that pretreatment with carbimazole reduces the degree of radiation induced thyroid damage.

Aged↗
PubMed1983

Transient hypothyroidism following radioiodine therapy for thyrotoxicosis.

A prospective study of thyroid function including serial tracer radioisotope uptake measurements in 55 patients treated with 131I therapy is described. Five patients had an episode of transient hypothyroidism within eight months of treatment: in three of these patients this was due to impaired organification of iodide, with normal iodide trapping by the thyroid (as measured by a twenty minute 123I uptake) being preserved. In contrast, in all patients who developed permanent hypothyroidism, iodide trapping was markedly diminished and did not recover. It is suggested that hypothyroidism due to organification failure following 131I therapy is potentially short-lived; where hypothyroidism is associated with gross impairment of iodide trapping, recovery is unlikely. Early iodine uptake measurements may be of value in selecting those patients whose hypothyroidism is transient and who do not require permanent thyroid hormone replacement.

Female↗
PubMed1983

Accumulation of thiourylene antithyroid drugs in mouse salivary gland.

[35S]Methimazole and [35S]propylthiouracil were shown to accumulate in mouse submandibular gland in vivo, with maximal tissue: plasma ratios being achieved at the lowest dose of drug studied (0.1 microgram/animal). Autoradiography of submandibular glands showed that the drugs were localized to the intralobular ductal epithelium and within the lumen of the convoluted granular tubule, which was identical to the localization of radiolabelled iodide. Histochemical studies indicated that this was the site of peroxidase activity within the gland. Drug accumulation persisted when iodide trapping was competitively inhibited using perchlorate. These data suggest that antithyroid drug accumulation by this tissue is not dependent on the anion trap; the localization of drug and iodide at the site of peroxidase activity suggest that this may be an important factor in the mechanism of drug accumulation, possibly related to subsequent drug metabolism.

Animals↗
PubMed1983

Influence of sodium perchlorate on thiourylene antithyroid drug accumulation in mice.

Radiolabelled [35S]propylthiouracil and [35S]methimazole were shown to accumulate in mouse thyroid gland in vivo, with maximal tissue/plasma ratios and maximal intrathyroidal levels of 35S-labelled drug being seen at the lowest dose of drug studied (0.1 micrograms/animal). Pretreatment with sodium perchlorate (10 mg) abolished iodide trapping by the thyroid and caused a fall in accumulation of both [35S]methimazole and [35S]propylthiouracil, although this effect was not seen at higher doses of drug, when tissue/plasma ratios approached unity. These data suggest that thiourylene antithyroid drug accumulation by the thyroid gland does not depend directly on the anion trap, and it is suggested that this accumulation might depend on subsequent intrathyroidal drug metabolism.

Animals↗
PubMed1982

Defects in intrathyroid binding of iodine and the perchlorate discharge test.

The kinetics of [123I]iodide uptake were studied when organification of iodine by the thyroid gland was normal and when this binding function was diminished by drugs or disease. Each study was terminated by a sodium perchlorate discharge test (300--600 mg iv) at 60 min or, in some cases, 10--30 min. The results confirmed that binding takes place rapidly in the uninhibited gland with the binding rate constant being at least 0.150 min-1. Discharge from the uninhibited gland is less than 3.5% of the gland uptake when perchlorate is given 60 min after the radioiodide. Subjects with an intrinsic binding defect manifested discharges of 11% of greater of the 60 min uptake and the estimated binding rate constants ranged from 0.003--0.057 min-1. Thyrotoxic subjects receiving 5 mg carbimazole twice daily manifested discharges ranging from 5.4--64.2%, and in those receiving 20 mg twice daily the observed discharges were 67.6--94.6% of the 60 min uptake. The study shows that a correctly performed perchlorate discharge test will detect minimal inhibition of iodine binding. An important factor is the duration of the follow-up period after perchlorate is given. In some of the cases studied discharge was not complete until 60 min after the perchlorate.

Binding Sites↗
PubMed1981

Intrathyroidal iodide binding rates and plasma methimazole concentrations in hyperthyroid patients on small doses of carbimazole.

1 The effect of small doses of carbimazole on the binding rate constant of intrathyroidal iodide, plasma methimazole concentrations and circulating thyroid hormone concentrations in five hyperthyroid patients is presented. 2 In all patients there was a marked reduction in iodide binding with carbimazole doses as low as 5 to 10 mg daily. 3 In three patients little further reduction in the observed binding rate occurred with daily doses in excess of 10 mg despite progressive increases in plasma methimazole concentrations. 4 At the end of 4 weeks' treatment with 10 mg carbimazole daily, the reduction in thyroid hormone concentrations and clinical improvement were such as to suggest that this dose may be an effective starting dose in many patients.

Adult↗
PubMed1980

Quantitation of thyroidal binding of iodide by compartmental analysis verified by an intravenous perchlorate discharge test.

Compartmental analysis was applied to 123I-iodide uptake data to quantitate iodine binding in the human thyroid gland. The method allowed for arterio/venous differences in plasma tracer level and for an "instantaneous" phase of thyroid uptake. Results were checked by an intravenous perchlorate discharge test. Observations in eleven normal and untreated thyrotoxic subjects confirmed earlier findings that iodine binding takes place rapidly, the binding rate constant being much greater than the exit rate constant. A lower limit of 0.15 min-1 for the binding rate constant in the uninhibited gland was estimated from the observations in one subject who demonstrated a small perchlorate discharge. The method was used in the study of eight subjects with an intrinsic binding defect and of twenty-four thyrotoxic subjects being treated with 5 mg or 20 mg carbimazole, twice daily. Binding rate constants (range 0.003--0.105 min-1) were typically less than the exit rate constants (range 0.027--0.156 min-1), the net clearance of iodide ranging from 1.5 to 67.9% of the unidirectioinal clearance, compared to 72% in the uninhibited gland. The method proved useful in assessing the severity of an intrinsic binding defect and in the investigation of lack of response to antithyroid drug therapy.

Computers↗
PubMed1980

Unexpected differences in early thyroidal trapping of iodide and pertechnetate.

Compartmental analysis was applied to simultaneously acquired 132-I-iodide and 99mTc-pertechnetate thyroid uptake data. The method allowed for arterio/venous differences in plasma tracer level and for an 'instantaneous' phase of thyroid uptake. Observations in four thyrotoxic patients, before and during antithyroid drug therapy, revealed greater 'instantaneous' uptake of TcO4-. The results also revealed that 'instantaneous' uptake of both I- and TcO4- may increase over the first six months of drug therapy. These findings could not be explained by the estimates of unidirectional clearance which were greater for I- and varied little during the early stages of drug therapy.

Antithyroid Agents↗
PubMed1980

The pharmacokinetics of methimazole after oral administration of carbimazole and methimazole, in hyperthyroid patients.

1 Methimazole plasma concentrations were measured in two groups of hyperthyroid subjects after the oral administration of either carbimazole or methimazole. 2 With the HPLC method it was also possible to measure the concentration of a methimazole metabolite, 3-methyl-2-thiohydantoin in one patient. 3 Large interindividual differences were observed, especially within the carbimazole group. 4 Incomplete absorption of carbimazole could explain particular high apparent volumes of distribution and apparent clearances.

Administration, Oral↗
PubMed1980

The pharmacokinetics of methimazole in pregnant patients after oral administration of carbimazole.

1 A high performance liquid chromatographic (HPLC) method was used to study the pharmacokinetics of methimazole after oral administration of carbimazole to women in various stages of pregnancy. 2 In one patient it was possible to conduct the study in the first and third timesters: there was an appreciable increase in the apparent clearance of methimazole. 3 Based on the assumption of complete absorption and hydrolysis of carbimazole to methimazole the mean apparent clearance was found to be significantly higher in pregnant patients receiving 10 mg carbimazole than in non-pregnant patients receiving the same dose.

Administration, Oral↗
PubMed1980

Comparison of antithyroid drug metabolism in the rat and guinea pig.

The thyroid accumulation, metabolism and urine excretion of (35S) propylthiouracil was compared in the guinea pig and the rat. Per gram thyroid tissue, the guinea pig thyroid took up much less drug than the rat, metabolised it faster and had a shorter t 1/2 for total 35S and free (35S) propylthiouracil. Liver metabolism, clearance of the drug from the serum and excretion in the urine were also considerably faster in the guinea pig. It is likely that a much larger dose of propylthiouracil would need to be administered to induce goitre in the guinea pig than is necessary in the rat.

Animals↗